GLP-1类似物与2型糖尿病及其慢性并发症的研究进展
摘要
胰升糖素样肽1(glucagons-like peptide-1,GLP-1)是主要由肠道L细胞分泌的一种胃肠道激素,具有刺激胰岛β细胞葡萄糖介导的胰岛素分泌,抑制胰升糖素分泌,减少肝葡萄糖输出,延缓胃内容物排空,改善外周组织对胰岛素的敏感性,抑制食欲及摄食等作用,其可被二肽基肽酶Ⅳ(dipeptidy1 proteaseⅣ,DPP-Ⅳ)降解,半衰期极短,限制了其临床应用。GLP-1类似物克服了GLP-1 T1 /2短的缺点,DPP-Ⅳ抑制剂抑制GLP-1的降解,给糖尿病治疗带来新的契机。近来研究还发现,GLP-1类似物和DPP-Ⅳ抑制剂对循环系统及神经系统具有保护作用,加强这方面的研究可能会为临床上糖尿病及其相关心血管疾病、神经系统疾病的治疗带来新的希望。依克那肽(exenatide)作为首个获准的GLP-1类似物,目前已经进行了大量临床研究。本文就GLP-1类似物作用机制及其对2型糖尿病及其慢性并发症的治疗及应用前景作一综述。
GLP-1 is an incretin hormone secreted from enteroendocrine L cells and pancreatic cells in response to ingested nutrients.physiological functions include increaseing insulin secretion from the pancreas in a glucose-dependent manner,decreaseing glucagon secretion from the pancreas,increaseing beta cells mass and insulin gene expression,inhibiting acid secretion and gastric emptying in the stomach,and decreasing food intake by increasing satiety.But it is rapidly inactivated by the enzyme dipeptidyl peptidaseⅣ(DPP-Ⅳ),which greatly limits its clinical application.GLP-1 analogs overcome the disadvantage of short T1/2 of GLP-1,and give the treatment for diabetes a new opportunity.DPP-Ⅳinhibitors inhibit the degradation of GLP-1.It has been demonstrated recently that GLP-1 analogues and DPP-Ⅳinhibitor play a protective role in the circulatory system and nervous system,These observations may subject to results of future studies translate into improved cardiovascular and neuval outcomes in this vulnerable patient population.Exenatide,as a first approved GLP-1 analogues,has conducted a large number of clinical trial.This article summarizes current concepts of GLP-1,s action and highlights the potential therapeutic utility for the treatment of Diabetes mellitus and its chronic complications.
GLP-1 is an incretin hormone secreted from enteroendocrine L cells and pancreatic cells in response to ingested nutrients.physiological functions include increaseing insulin secretion from the pancreas in a glucose-dependent manner,decreaseing glucagon secretion from the pancreas,increaseing beta cells mass and insulin gene expression,inhibiting acid secretion and gastric emptying in the stomach,and decreasing food intake by increasing satiety.But it is rapidly inactivated by the enzyme dipeptidyl peptidaseⅣ(DPP-Ⅳ),which greatly limits its clinical application.GLP-1 analogs overcome the disadvantage of short T1/2 of GLP-1,and give the treatment for diabetes a new opportunity.DPP-Ⅳinhibitors inhibit the degradation of GLP-1.It has been demonstrated recently that GLP-1 analogues and DPP-Ⅳinhibitor play a protective role in the circulatory system and nervous system,These observations may subject to results of future studies translate into improved cardiovascular and neuval outcomes in this vulnerable patient population.Exenatide,as a first approved GLP-1 analogues,has conducted a large number of clinical trial.This article summarizes current concepts of GLP-1,s action and highlights the potential therapeutic utility for the treatment of Diabetes mellitus and its chronic complications.
引文
1 Drucker D. Enhacing incretin action for the treatment of type 2 diabetes. Diabetes Care, 2003, 26(14): 2929-2940
2 Perfettj R,Merkel. Glucagon-like peptide-1:a major regulator of pancreaticβ-cell function. Eur J Endocrinol, 2000, 143(16): 717-725
3 Schwartz JG,Green GM,Guan D,et al. Rapid gastric empty- ing of a solid pancake meal in type II diabetic patients. Diabetes Care, 1996, 19(5)468-371
4 Heller RS,Kieffer TJ,Habener JF. Insulinotropic glucagon- like peptide I receptor expression in glucagon-producing alpha-cells of the rat endocrine pancreas.Diabetes, 1997, 46(5): 785-791
5 Porret B A, Bühler L, Deng S P, et al. Cloning and func - tional expressionof the human islet GLP- 1 receptor: demo- nstration that exendin-4 is an agonist and exendin(9-39) an antagonist of the receptor. Diabetes, 1993, 42(7): 1678- 1682
6 Hansen I, Deacon C F, Orskov C, et al. Glucagon- like pep- tide1(7- 36)amide is transformed to glucagon- like peptide- 1 (9- 36)amideby dipeptidyl peptidaseⅣin the capillaries supplying the I cellsof porcine intestine. Endocrinology, 1999, 140(2): 53- 56
7 Parkes D, Jodka C, Smith P, et al. Pharmacokinetic actions of exendin-4 in the rat: comparison with glucagon - likepeptide - 1. Drug Dev Res, 2001, 53(4): 260- 267
8 Lester LB,Langeberg LK,Scott JD. Anchoring of protein kinase Afacilitates hormone-mediated insulin secretion. Proc Natl AcadSci USA, 1997, 94(26): 14942-14947
9李晓丽,林东子,张志珍.GLP-1与糖尿病基因治疗. MedMol Biol,2008,5 (5):449-453
10 Holz GG. Epac: A new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transdu ct- ion in the pancreatic beta-cell. Diabetes, 2004, 53(1): 5-13
11 Li LX,MacDonald PE,Ahn DS,et al. Role of phosphatidyl- inositol 3-kinasegamma in the beta-cell: interactions with glucagon-like peptide-1. Endocrinology, 2006, 147(7): 3318-3325
12 Gromada J,Bokvist K,Ding WG,et al. Glucagon-like peptide 1(7-36) amide stimulates exocytosis in human pancreatic beta-cells by both proximal and distal regulatory steps in stimulus-secretion coupling. Diabetes, 1998, 47(2): 57-65
13 Greig NH, Holloway HW, De Ore KA, et al. Once daily injection of exendin - 4 to diabetic mice achieves long - term beneficial effects on blood glucose concentrations. D iabetologia, 1999, 42(5) : 45-50
14 Parkes DG, Pittner R, Jodka C, et al. Insulinotrop ic actions of exendin-4 and glucagons-like peptide-1 in vivo and in vitro. M etabolism , 2001, 50(4): 583-589
15 Fehse F, trautmannM, Holst JJ, et al. Exenatide augments first– and second - phase insulin secretion in response tointravenous glucose in subjectswith type 2 diabetes. Clin Endocrinol Metab, 2005, 90(23): 5991 - 5997
16 MooreMC, Cherrington AD. Regulation of net hepatic glucose up take: interaction of neural and pancreatic mechanisms. Reprod NutrDev,1996, 36(11): 399-406
17 Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab, 2004, 287 (2) : 199-206
18 Deacon CF. Therapeutic strategies based on glucagon - like pep tide 1. Diabetes, 2004, 53 (9) : 2181-2189
19 Nauck MA ,Kleine N ,Orskov C , et al . Normalization of hyperglycaemia by exogenous glucagons-like peptide-1 (7236 amide) in type 2 (non-in-sulin-dependent) diabetic patients. Diabetologia, 1993, 36 (8):741-744
20 Willms B, Werner J, Holst JJ, et al. Gastric emptying, glucose responses,and insulin secretion after a liquid test meal: effect of exogenous glucagon-like peptide 1(7- 36) amide in type 2 diabetic patients. Clin Endocrinol Metab, 1996, 81(9): 327- 332
21 Little TJ ,Pilichiewicz AN ,Russo A , et al . Effects of intra- venous glucagons-like peptide-1 on gastric emptying and intragastric distribution in healthy subjects :relationships with postprandial glycemic and insulinemic responses. Clin Endocrinol Metab, 2006, 91(5): 1916-1923
22 Franklin I, Gromada J , Gjinovci A, et al.β-cell-secretory products activateα-cell ATP dependent potassium channels to inhibit glucagon release. Diabetes, 2005, 54(6): 1808 -1815
23 Meier JJ, Gallwitz B, Salmen S, et al. Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagons like peptide 1 in patients with typ2 diabetes. J Clin Endocrinol Metab, 2003, 88(6): 2719 - 2725.
24 Little TJ ,Pilichiewicz AN ,Russo A , et al . Effects of intravenous glucagon2like peptide21 on gastric emptying and intragastric distribution in healthy subjects :relationships with postprandial glycemic and insulinemic responses. Clin Endocrinol Metab, 2006, 91(5): 1916-1923.
25 Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6- week course of glucagons-like peptide 1 on glycemic control, insulin sensitivity, and beta - cell function in type 2 diabetes :A parallel-group study. Lancet ,2002, 359(12): 824 - 30.
26 Salomon B, Lenschow D J, Rhee L, et al. B7 /CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity, 2000, 121(9): 431- 440.
27 Willms B, Werner J, Holst JJ, et al. Gastric emptying, glucose responses,and insulin secretion after a liquid test meal: effect of exogenous glucagon-like peptide 1(7- 36) amide in type 2 diabetic patients. Clin Endocrinol Metab, 1996, 81(8): 327- 332
28 Zeender E, Maedler K, Bosco D. Pioglitazone and sodiumsalicylate protect human beta-cells against apoptosis and impaired function induced by glucose and interleukin-1beta. J Clin Endocrinol Metab 2004(89): 5059-66
29圣斌. GLP-1在摄食和胃肠道生理功能中的作用.胃肠病学和肝病学杂志, 2005, 14(2): 212-214.
30 Farilla L ,Hui H ,Bertolotto C ,et al .Glucagon-like-peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats. Endocrinology, 2002, 143(19) :4397-4408.
31 Li Y,Hansotia T , Yusta B ,et al . Glucagon-like-peptide-1 receptor signaling modulatesβcell apoptosis. Biol Chem, 2003, 278(7): 471-478
32 Hui H ,Nourparvar A , Zhao X, et al . Glucagon- like–pep- tide-1 inhibits apoptosis of insulin secreting cells via a cyclic 5′-adenosine monophosphate-dependent protein kinase A- and a phosphastidylinositol 3-kinase-dependent pathway. Endocrinology, 2003, 144(26): 1444-1455
33 Kwon G,Pappan KL ,Marshall CA ,et al . cAMP dose- dependently prevents palmitate-induced apoptosis by both protein kinase A- and cAMP guanine nucleotide exchange factor-dependent pathways inβ-cells. Biol Chem, 2004, 279 (12): 8938-8945
34 Li L ,El-Kholy W,Rhodes CJ ,et al . Glucagon-like peptide-1 protects beta cells from cytokine-induced apoptosis and necrosis :role of protein kinase B. Diabetologia, 2005, 48(3): 1339-1349
35王燕萍,刘礼斌. GLP-1对胰岛β细胞保护作用的研究进展.国际内分泌代谢杂志,2007, 27(2):98-100
36 Wang Q ,Li L ,Xu E ,et al . Glucagon-like peptide-1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells. Diabetologia, 2004, 47(12): 478-487
37 Wang Q ,Brubaker PL. Glucagon2like2peptide21 treatment delays the on-set of diabetes in 8 week-old db/ db mice. Diabetologia, 2002, 45(20): 1263-1273
38 Jhala US ,Canettieri G,Screaton RA ,et al . cAMP promotes pancreatic Beta cell survival via CREB-mediated induction of IRS2. Genes Dev, 2003, 17(5):1575-1580
39 Jhala US ,Canettieri G,Screaton RA ,et al . cAMP promotes pancreatic beta cell survival via CREB2mediated induction of IRS2. Genes Dev, 2003, 17(6): 1575-1580.
40 Regenholt S ,Molddrup A ,Blume N ,et al . The long-acting glucagon-like-peptide-1 analogue , liraglutide , inhibits beta cell apoptosis in vitro. Biochem Biophys Res Commun , 2005, 330(2): 577-584.
41 Xu G, Stoffers D A, Habener J F, et al. Exendin- 4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rat. Diabete, 1999, 48(22): 2270- 2276
42 Tourrel C, Bailbe D, Meile NJ, et al. Glucagon-like peptide- 1 and exendin-4 stimulateβ-cell neogenesis in strepto- zotocin– treated newborn rats resulting in persisten-tlyimp roved glucose homeostasis at adult age. Diabetes, 2001,50(5): 1562- 1570
43 Dutta S, Bonner -Weir S, Montminy M, et al. Regulatory factor linked to late- onset- diabetes. Nature, 1998, 1031(11)392: 560
44 Smith P, Young A A, Gedulin B R. Exendin- 4 injections a meliorated progression of fasting hyperglycemia and elevation of HbAlcin diabetic fally Zucker(ZDF) rats. Diabetes, 2001, 50(2): 21-34
45 Gedulin B R, Smith P, Young A A. Exendin- 4 injections: Ameliorated progression of fasting hyperglycemia, e1evation of fructosamine HbAlc, Total cholesterol and increased C- peptide level in Prediabetic Zucker diabetic fatty rats. 37th Annu Meet Eur Assoc Study Diabetes, 2001, 143(1):75-81
46 Perry T, Haughey NJ, MattsonMP, et al. Protection and reversal of exocitotoxic neuronal damage by glucagons-like peptide-1 and exendin24. Pharmacol Exp Ther, 2002, 302 (3): 68-81
47 Hongbin Liu, Yunshan Hu, Richard W S. Glucagon-like peptide-1 attenuates tumour necrosis factor-a-mediated induction of plasmogen activator inhibitor-1 expression. J Clin Endocrinol Metab. 2008, 196(2):57–65
48黄昭,黄昭穗,胰高血糖素样肽-1类似物Exenatide的临床应用进展. 2008, 36(2):296-299
49 Erry T, LahiriDK, Chen D, et al. A novel neurotrophic p roperty of glucagon-like pep tide 1: a p romoter of nerve growth factor - mediated differentiation in PC12 cells. Pharmacol Exp Ther, 2002,300(13) : 958-966
50沙伟伟,谢云.胰高血糖素样肽1的研究.医学综述, 2008, 14(1): 24-26
51 Perry T, Haughey NJ, MattsonMP, et al. Protection and reversal of excitotoxic neuronal damage by glucagon - like pep tide - 1 and exendin - 4. Pharm acol Exp Ther, 2002, 302 (7): 881-888
52 During MJ, Cao L, Zuzga DS, et al. Glucagon - like pep tide - 1 receptor is involved in learning and neurop rotection. N at Med,2003, 9(17): 1173-1179
53 TracyAnn Perry, Harold W. Holloway, Ananda Weerasu ri- ya,et al. Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy, Exp Neurol. 2007 , 203(2): 293–301
54 Perry T, Holloway H , Weerasuriya A, et al. Evidence of GLP -1-mediated neurop rotection in an animal model of pyridoxine– induced eripheral ensory neuropathy. Exp N eurol, 2006, 87(11): 138– 156
55 Peon T, Nelson P, Shen L, et al. Exenatide improves g1ycemic control and reduces body weight in subjects with type 2 diabetes: a dose- ranging study. Diabetes Technol Ther, 2005, 7(3): 467- 477
56 Kendall D M, Riddle M C, Rosenstock J, et al. Effects of exenatide (exendin- 4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care, 2005, 28(5): 1083-1091.
57 Ralph A, Ratner R E, Han J, et al. Efects of exenat I d e(exendin-4) on glycemic control and weight over 30 weeks in metformin- treated patients with type 2 diabetes. Diabetes Care, 2005, 28(3): 1092- 1100
58 Fineman M S, Bicsak T A, Shen L Z, et al. Effect on glycemic control of synthetic exendin- 4 (AC2993) additive to existing metformin and /or sulfonylurea treatment in patients with type 2 diabetes. Physiol Behav Diabetes Care, 2003, 26(7): 237-240
2 Perfettj R,Merkel. Glucagon-like peptide-1:a major regulator of pancreaticβ-cell function. Eur J Endocrinol, 2000, 143(16): 717-725
3 Schwartz JG,Green GM,Guan D,et al. Rapid gastric empty- ing of a solid pancake meal in type II diabetic patients. Diabetes Care, 1996, 19(5)468-371
4 Heller RS,Kieffer TJ,Habener JF. Insulinotropic glucagon- like peptide I receptor expression in glucagon-producing alpha-cells of the rat endocrine pancreas.Diabetes, 1997, 46(5): 785-791
5 Porret B A, Bühler L, Deng S P, et al. Cloning and func - tional expressionof the human islet GLP- 1 receptor: demo- nstration that exendin-4 is an agonist and exendin(9-39) an antagonist of the receptor. Diabetes, 1993, 42(7): 1678- 1682
6 Hansen I, Deacon C F, Orskov C, et al. Glucagon- like pep- tide1(7- 36)amide is transformed to glucagon- like peptide- 1 (9- 36)amideby dipeptidyl peptidaseⅣin the capillaries supplying the I cellsof porcine intestine. Endocrinology, 1999, 140(2): 53- 56
7 Parkes D, Jodka C, Smith P, et al. Pharmacokinetic actions of exendin-4 in the rat: comparison with glucagon - likepeptide - 1. Drug Dev Res, 2001, 53(4): 260- 267
8 Lester LB,Langeberg LK,Scott JD. Anchoring of protein kinase Afacilitates hormone-mediated insulin secretion. Proc Natl AcadSci USA, 1997, 94(26): 14942-14947
9李晓丽,林东子,张志珍.GLP-1与糖尿病基因治疗. MedMol Biol,2008,5 (5):449-453
10 Holz GG. Epac: A new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transdu ct- ion in the pancreatic beta-cell. Diabetes, 2004, 53(1): 5-13
11 Li LX,MacDonald PE,Ahn DS,et al. Role of phosphatidyl- inositol 3-kinasegamma in the beta-cell: interactions with glucagon-like peptide-1. Endocrinology, 2006, 147(7): 3318-3325
12 Gromada J,Bokvist K,Ding WG,et al. Glucagon-like peptide 1(7-36) amide stimulates exocytosis in human pancreatic beta-cells by both proximal and distal regulatory steps in stimulus-secretion coupling. Diabetes, 1998, 47(2): 57-65
13 Greig NH, Holloway HW, De Ore KA, et al. Once daily injection of exendin - 4 to diabetic mice achieves long - term beneficial effects on blood glucose concentrations. D iabetologia, 1999, 42(5) : 45-50
14 Parkes DG, Pittner R, Jodka C, et al. Insulinotrop ic actions of exendin-4 and glucagons-like peptide-1 in vivo and in vitro. M etabolism , 2001, 50(4): 583-589
15 Fehse F, trautmannM, Holst JJ, et al. Exenatide augments first– and second - phase insulin secretion in response tointravenous glucose in subjectswith type 2 diabetes. Clin Endocrinol Metab, 2005, 90(23): 5991 - 5997
16 MooreMC, Cherrington AD. Regulation of net hepatic glucose up take: interaction of neural and pancreatic mechanisms. Reprod NutrDev,1996, 36(11): 399-406
17 Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab, 2004, 287 (2) : 199-206
18 Deacon CF. Therapeutic strategies based on glucagon - like pep tide 1. Diabetes, 2004, 53 (9) : 2181-2189
19 Nauck MA ,Kleine N ,Orskov C , et al . Normalization of hyperglycaemia by exogenous glucagons-like peptide-1 (7236 amide) in type 2 (non-in-sulin-dependent) diabetic patients. Diabetologia, 1993, 36 (8):741-744
20 Willms B, Werner J, Holst JJ, et al. Gastric emptying, glucose responses,and insulin secretion after a liquid test meal: effect of exogenous glucagon-like peptide 1(7- 36) amide in type 2 diabetic patients. Clin Endocrinol Metab, 1996, 81(9): 327- 332
21 Little TJ ,Pilichiewicz AN ,Russo A , et al . Effects of intra- venous glucagons-like peptide-1 on gastric emptying and intragastric distribution in healthy subjects :relationships with postprandial glycemic and insulinemic responses. Clin Endocrinol Metab, 2006, 91(5): 1916-1923
22 Franklin I, Gromada J , Gjinovci A, et al.β-cell-secretory products activateα-cell ATP dependent potassium channels to inhibit glucagon release. Diabetes, 2005, 54(6): 1808 -1815
23 Meier JJ, Gallwitz B, Salmen S, et al. Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagons like peptide 1 in patients with typ2 diabetes. J Clin Endocrinol Metab, 2003, 88(6): 2719 - 2725.
24 Little TJ ,Pilichiewicz AN ,Russo A , et al . Effects of intravenous glucagon2like peptide21 on gastric emptying and intragastric distribution in healthy subjects :relationships with postprandial glycemic and insulinemic responses. Clin Endocrinol Metab, 2006, 91(5): 1916-1923.
25 Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6- week course of glucagons-like peptide 1 on glycemic control, insulin sensitivity, and beta - cell function in type 2 diabetes :A parallel-group study. Lancet ,2002, 359(12): 824 - 30.
26 Salomon B, Lenschow D J, Rhee L, et al. B7 /CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity, 2000, 121(9): 431- 440.
27 Willms B, Werner J, Holst JJ, et al. Gastric emptying, glucose responses,and insulin secretion after a liquid test meal: effect of exogenous glucagon-like peptide 1(7- 36) amide in type 2 diabetic patients. Clin Endocrinol Metab, 1996, 81(8): 327- 332
28 Zeender E, Maedler K, Bosco D. Pioglitazone and sodiumsalicylate protect human beta-cells against apoptosis and impaired function induced by glucose and interleukin-1beta. J Clin Endocrinol Metab 2004(89): 5059-66
29圣斌. GLP-1在摄食和胃肠道生理功能中的作用.胃肠病学和肝病学杂志, 2005, 14(2): 212-214.
30 Farilla L ,Hui H ,Bertolotto C ,et al .Glucagon-like-peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats. Endocrinology, 2002, 143(19) :4397-4408.
31 Li Y,Hansotia T , Yusta B ,et al . Glucagon-like-peptide-1 receptor signaling modulatesβcell apoptosis. Biol Chem, 2003, 278(7): 471-478
32 Hui H ,Nourparvar A , Zhao X, et al . Glucagon- like–pep- tide-1 inhibits apoptosis of insulin secreting cells via a cyclic 5′-adenosine monophosphate-dependent protein kinase A- and a phosphastidylinositol 3-kinase-dependent pathway. Endocrinology, 2003, 144(26): 1444-1455
33 Kwon G,Pappan KL ,Marshall CA ,et al . cAMP dose- dependently prevents palmitate-induced apoptosis by both protein kinase A- and cAMP guanine nucleotide exchange factor-dependent pathways inβ-cells. Biol Chem, 2004, 279 (12): 8938-8945
34 Li L ,El-Kholy W,Rhodes CJ ,et al . Glucagon-like peptide-1 protects beta cells from cytokine-induced apoptosis and necrosis :role of protein kinase B. Diabetologia, 2005, 48(3): 1339-1349
35王燕萍,刘礼斌. GLP-1对胰岛β细胞保护作用的研究进展.国际内分泌代谢杂志,2007, 27(2):98-100
36 Wang Q ,Li L ,Xu E ,et al . Glucagon-like peptide-1 regulates proliferation and apoptosis via activation of protein kinase B in pancreatic INS-1 beta cells. Diabetologia, 2004, 47(12): 478-487
37 Wang Q ,Brubaker PL. Glucagon2like2peptide21 treatment delays the on-set of diabetes in 8 week-old db/ db mice. Diabetologia, 2002, 45(20): 1263-1273
38 Jhala US ,Canettieri G,Screaton RA ,et al . cAMP promotes pancreatic Beta cell survival via CREB-mediated induction of IRS2. Genes Dev, 2003, 17(5):1575-1580
39 Jhala US ,Canettieri G,Screaton RA ,et al . cAMP promotes pancreatic beta cell survival via CREB2mediated induction of IRS2. Genes Dev, 2003, 17(6): 1575-1580.
40 Regenholt S ,Molddrup A ,Blume N ,et al . The long-acting glucagon-like-peptide-1 analogue , liraglutide , inhibits beta cell apoptosis in vitro. Biochem Biophys Res Commun , 2005, 330(2): 577-584.
41 Xu G, Stoffers D A, Habener J F, et al. Exendin- 4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rat. Diabete, 1999, 48(22): 2270- 2276
42 Tourrel C, Bailbe D, Meile NJ, et al. Glucagon-like peptide- 1 and exendin-4 stimulateβ-cell neogenesis in strepto- zotocin– treated newborn rats resulting in persisten-tlyimp roved glucose homeostasis at adult age. Diabetes, 2001,50(5): 1562- 1570
43 Dutta S, Bonner -Weir S, Montminy M, et al. Regulatory factor linked to late- onset- diabetes. Nature, 1998, 1031(11)392: 560
44 Smith P, Young A A, Gedulin B R. Exendin- 4 injections a meliorated progression of fasting hyperglycemia and elevation of HbAlcin diabetic fally Zucker(ZDF) rats. Diabetes, 2001, 50(2): 21-34
45 Gedulin B R, Smith P, Young A A. Exendin- 4 injections: Ameliorated progression of fasting hyperglycemia, e1evation of fructosamine HbAlc, Total cholesterol and increased C- peptide level in Prediabetic Zucker diabetic fatty rats. 37th Annu Meet Eur Assoc Study Diabetes, 2001, 143(1):75-81
46 Perry T, Haughey NJ, MattsonMP, et al. Protection and reversal of exocitotoxic neuronal damage by glucagons-like peptide-1 and exendin24. Pharmacol Exp Ther, 2002, 302 (3): 68-81
47 Hongbin Liu, Yunshan Hu, Richard W S. Glucagon-like peptide-1 attenuates tumour necrosis factor-a-mediated induction of plasmogen activator inhibitor-1 expression. J Clin Endocrinol Metab. 2008, 196(2):57–65
48黄昭,黄昭穗,胰高血糖素样肽-1类似物Exenatide的临床应用进展. 2008, 36(2):296-299
49 Erry T, LahiriDK, Chen D, et al. A novel neurotrophic p roperty of glucagon-like pep tide 1: a p romoter of nerve growth factor - mediated differentiation in PC12 cells. Pharmacol Exp Ther, 2002,300(13) : 958-966
50沙伟伟,谢云.胰高血糖素样肽1的研究.医学综述, 2008, 14(1): 24-26
51 Perry T, Haughey NJ, MattsonMP, et al. Protection and reversal of excitotoxic neuronal damage by glucagon - like pep tide - 1 and exendin - 4. Pharm acol Exp Ther, 2002, 302 (7): 881-888
52 During MJ, Cao L, Zuzga DS, et al. Glucagon - like pep tide - 1 receptor is involved in learning and neurop rotection. N at Med,2003, 9(17): 1173-1179
53 TracyAnn Perry, Harold W. Holloway, Ananda Weerasu ri- ya,et al. Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy, Exp Neurol. 2007 , 203(2): 293–301
54 Perry T, Holloway H , Weerasuriya A, et al. Evidence of GLP -1-mediated neurop rotection in an animal model of pyridoxine– induced eripheral ensory neuropathy. Exp N eurol, 2006, 87(11): 138– 156
55 Peon T, Nelson P, Shen L, et al. Exenatide improves g1ycemic control and reduces body weight in subjects with type 2 diabetes: a dose- ranging study. Diabetes Technol Ther, 2005, 7(3): 467- 477
56 Kendall D M, Riddle M C, Rosenstock J, et al. Effects of exenatide (exendin- 4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care, 2005, 28(5): 1083-1091.
57 Ralph A, Ratner R E, Han J, et al. Efects of exenat I d e(exendin-4) on glycemic control and weight over 30 weeks in metformin- treated patients with type 2 diabetes. Diabetes Care, 2005, 28(3): 1092- 1100
58 Fineman M S, Bicsak T A, Shen L Z, et al. Effect on glycemic control of synthetic exendin- 4 (AC2993) additive to existing metformin and /or sulfonylurea treatment in patients with type 2 diabetes. Physiol Behav Diabetes Care, 2003, 26(7): 237-240